Diuretics and Antidiuretics 205to reduce glomerular filtration rate by their
action to reduce blood volume, also decrease
positive free water formation. Although this
response is less than that seen with ADH-
deficient diabetes insipidus patients treated
with ADH, it is sufficient to reduce
significantly urinary frequency and water
consumption.
Pharmacokinetics
All thiazides and related compounds are
well absorbed from the GIT and begin to
produce diuresis within one hour after oral
administration, but the duration is variable,
which are due to variation in rates of renal
tubular secretion and clearance, metabolism,
and enterohepatic circulation. Approximately
50 percent of an oral dose is excreted in urine
within 6 hours. Most of the agents undergo little
hepatic metabolism and excreted as such.
However indapamide is extensively
metabolized.
Adverse Reactions
In the presence of severe renal and hepatic
disease, these drugs may precipitate renal
failure or hepatic coma. The most important
toxic effect associated with thiazide therapy
is hypokalemia and hypochloremic alkalosis.
The thiazides may induce hyperglyce-
mia and aggravate pre-existing diabetes
mellitus, the pharmacological effect of oral
hypoglycemic agents may also be reduced.
Occasionally, they can cause allergic
reactions like rashes, photosensitivity,
thrombocytopenic purpura, dermatitis etc.
Therapeutic Uses
- Edema: Thiazides are useful adjunctive
therapy in controlling the edema asso-
ciated with CHF and cirrhosis.- Hypertension: They are widely used in
the treatment of hypertension with or
without edema and often serve as the
first drug of choice. - Diabetes insipidus: They reduce urine
volume in both pituitary and renal dia-
betes insipidus. They are especially
valuable for the latter in which ADH is
ineffective.
HIGH-CEILING OR LOOP DIURETICS
These are the most efficacious agents
available for inducing marked water and
electrolyte excretion. The peak diuresis is far
greater than that observed maximally with
other diuretics. The drugs in this group
include furosemide, bumetanide and
ethacrynic acid and the main site of action
is the thick ascending limb of loop of Henle,
thus they are often called ‘loop diuretics.’
The high-ceiling diuretics act primarily
by inhibiting electrolyte reabsorption in the
thick ascending limb of the loop of Henle.
As much as 20% of the filtered Na+ may be
reabsorbed in the loop of Henle.
These agents bind to Cl– binding site of
Na+-K+-2Cl– cotransporter glycoprotein and
inhibit its transport function in ascending
limb of loop of Henle.
These agents tend to increase renal blood
flow without increasing filtration rate, which
reduces fluid and electrolyte reabsorption
in the proximal tubule and may augment the
initial diuretic response.Pharmacodynamics
After oral administration, the intense